Review of Safety of Thimerosal-Containing Vaccines: a Two- Phased Study of Computerized Health Maintenance Organization Databases (Pediatrics 2003)

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1 Review of Safety of Thimerosal-Containing Vaccines: a Two- Phased Study of Computerized Health Maintenance Organization Databases (Pediatrics 2003) Introduction Review of Verstraeten findings focused on autism Effects of inclusion/exclusion criteria upon autism findings Other subanalyses of autism-thimerosal Chronology of autism analyses Discussion of other concerns Update on planning for Autism Thimerosal study

2 Robert Davis, MD, MPH Professor University of Washington School of Medicine, Department of Pediatrics University of Washington School of Public Health, Department of Epidemiology Scientific Investigator Group Health Cooperative Center for Health Studies

3 Robert Davis, MD, MPH Current Funding Agency for Healthcare Research and Quality (AHRQ): Centers for Education and Research in Therapeutics Centers for Disease Prevention and Control: Vaccine Safety Datalink (VSD); Clinical Immunization Safety Assessment (CISA) University of Washington School of Public Health: Teaching

4 Robert Davis, MD, MPH Past Funding Includes: Federal: NIH, AHRQ, CDC Pharmaceutical: Merck, GlaxoSmithKline, Wyeth, Pfizer, Amgen Foundations: Packard, Culpepper

5 Safety of Thimerosal-Containing Vaccines: a Two-Phased Study of Computerized Health Maintenance Organization Databases Vaccine Safety Datalink (VSD) Partnership between CDC and seven Health Maintenance Organizations (HMOs) Large linked database including vaccination, clinic, hospital discharge and demographic data Initiated in 1991 Covers estimated 2.5% of U.S. population

6 Ethylmercury content of vaccines used in VSD study population Diphtheria, Tetanus, and Pertussis vaccines: 0 or 25 micrograms/dose Haemophilus influenzae B vaccines: 0, 12.5 or 25 micrograms/dose Hepatitis B vaccines: 12.5 micrograms/dose Polio, Measles, Mumps, Rubella, Varicella, and Pneumococcal vaccines: no thimerosal

7 Cumulative ethylmercury (EtHg) exposure from thimerosalcontaining vaccines in VSD study population Age at exposure Total Hg dose in the period Cumulative Hg at end of period 0-1 m 2-3 m 4-5 m 6-7 m 12.5 ug ug ug ug 12.5 ug ug 75 or 125 ug ug

8 Infants in VSD exceeding EPA mercury exposure limit 100% 80% 60% 40% 20% HMO A HMO B 0% Age in months

9 Two-phased Study Phase I: Screen range of neurodevelopmental and renal disorders Phase II: Re-assess associations encountered in phase I

10 Study methods Retrospective cohort study of automated vaccination and outcomes data Exposure: mercury from thimerosal-containing childhood vaccines at different ages Outcomes: range of plausible neurologic and renal disorders, including autism

11 Study population Born between 1992 and 1998 Born into one of two HMOs of VSD Continuously enrolled first year of life Received at least 2 polio vaccinations by 1 year of age Followed until December, 2000

12 Study exclusions LBW <2500 g Congenital or severe perinatal disorders, or mothers with serious medical problems of pregnancy

13 Exposure assessment Cumulative mercury exposure calculated from individual automated vaccination records (including vaccine type, manufacturer and lot number) Total ethylmercury exposure was modeled as continuous and categorical variable total ethylmercury exposure/12.5 ug Exposure periods assessed at: 1,3 and 7 months

14 Statistical analyses Proportional hazards models Separate for each HMOs Stratified on gender, year and month of birth at HMO A gender, year and month of birth, and clinic at HMO B Adjusted for health-care seeking behavior (restricted comparison group to children with at least 1 visit to clinic/ed at time of autism diagnosis)

15 Statistical analyses Person time began with First birthday at HMO A First birthday or January 1, 1995 (whichever came later) at HMO B Person-time censored on diagnosis date or last date of follow-up Temporary disenrollment allowed, but person time and diagnoses only used while child was enrolled

16 Medical record validation Reviewed 120 medical records of children with ICD-9 code of autism 81-92% showed the diagnosis was made by clinical or behavioral specialist

17 Results Autism (299.0) Total number 223 HMO A 21 HMO B 202 Mean age at diagnosis months Male 80%-90%

18 Total Birth Cohort at HMO A: Total Birth Cohort at HMO B: Not Continuously Enrolled 6,011 78,829 # Excluded due to Low Birthweight # Excluded Due to Congenital or Perinatal Conditions Continuously Enrolled during 1 st Year of Life: 17, ,363 Children whose Birthweight was >2500g: 16,358 2,469 28,133 Continuously Enrolled during 1 st Year of Life: 150,456 Children whose Birthweight was >2500g: 143,093 # Excluded Due to Receipt of < 2 Polio Vaccinations 552 No Severe Perinatal or Congenital Disorders: 13,889 Final Cohort, Excluding Children With <2 Polio Vaccinations: 13,337 4,127 No Severe Perinatal or Congenital Disorders: 114,960 Final Cohort, Excluding Children With <2 Polio Vaccinations: 110,833

19 Relative risk (95% CI) by 12.5 ug increase Hg exposure (HMO B) 1 month Hg 3 month Hg 7 month Hg (cumulative) (cumulative) (cumulative) Autism 1.16 (0.78, 1.71) 1.06 (0.88, 1.28) 1.00 (0.90, 1.09)

20 Relative risk for autism (95% CI) by category of Hg exposure (HMO B) 3 month RR (95% CI) N cumulative Hg (0.77, 3.34) 158 >= (0.55, 3.48) 33

21 Relative risk for autism (95% CI) by category of Hg exposure (HMO B) 7 month RR (95% CI) N cumulative Hg (0.62, 1.46) 148 >= (0.27, 1.52) 17

22 Review of Safety of Thimerosal-Containing Vaccines: a Two- Phased Study of Computerized Health Maintenance Organization Databases (Pediatrics 2003) Review of Verstraeten findings focused on autism Effects of inclusion/exclusion criteria upon autism findings Other subanalyses of autism-thimerosal Chronology of autism analyses Discussion of other concerns

23 Effect of congenital/perinatal exclusions HMO B (based on earlier analysis; n = 150) tcome 0-1 m 2-3 m 4-5 m 6-7 m 0-7 m y neurodevelopmental disorder ** ** 1.05 * ** ** 1.05 * tism mmering * 1.14 * * 1.21 * s * 1.23 ** 1.15 * * 1.18 * 1.14 * tention deficit disorder * * 1.06 * * 1.10 * *

24 Effect of not excluding any children (based on earlier analysis, HMO B 0-1 m 2-3 m 4-5 m 6-7 m 0-7 m tism l children (n = 215) lio >1 at 1 year ( n =213) low birth weight ( n = 196) dy cohort (n = 150)

25 Review of Safety of Thimerosal-Containing Vaccines: a Two- Phased Study of Computerized Health Maintenance Organization Databases (Pediatrics 2003) Review of Verstraeten findings focused on autism Effects of inclusion/exclusion criteria upon autism findings Other subanalyses of autism-thimerosal Chronology of autism analyses Discussion of other concerns

26 (Unadjusted) relative risks by increase of 12.5 ug ethylmercury chart verified diagnoses tcome 0-1 m 2-3 m 4-5 m 6-7 m 0-7 m eech delay HMO A eech delay HMO B 1.54 ** tism HMO B tention deficit disorder HMO B * *: p<0.05 **: p<0.01

27 Implicit adjustment for care-seeking behavior: DTP separate vs combined (based on earlier analysis of 150 cases) utcome RR 95 % CI utism tammering ics leep disorders motional disturbances ttention deficit disorder anguage delay peech delay lat feet or toe deformities *

28 Mrs Redwood s request Auti sm: RR + 95 % CI f or dif f er ent levels of cunmulative ethylmer cur y exposur e f r om thimer osal-containing vaccines in f ir st 7 months of lif e at HMO A and HMO B, <=25 ug 37.5 ug 50 ug 62.5 ug 75 ug 87.5 ug 100 ug ug 125 ug ug 150 ug ug 175 ug > 175 (n=1) (n=1) (n=0) (n=1) (n=24) (n=3) (n=55) (n=31) (n = 7) (n = 3) (n = 10) ( n= 0) (n=11) (n= 3) Cumulative ethylmer cur y exposur e (n=number of cases in categor y)

29 Review of Safety of Thimerosal-Containing Vaccines: a Two- Phased Study of Computerized Health Maintenance Organization Databases (Pediatrics 2003) Review of Verstraeten findings focused on autism Effects of inclusion/exclusion criteria upon autism findings Other subanalyses of autism-thimerosal Chronology of autism analyses Discussion of other concerns

30 Background 9/99: Thimerosal working group identified VSD study as priority 9-10/99: Protocol developed in collaboration with thimerosal working group and VSD PIs 11/99-2/00: Data analyses 3-4/00: VSD discussions of interim results, involving FDA

31 Background February 2000 Exposure at 3 mo 62 cases total RR 2.48 at >62.5 vs <37.5; p NS (CI not given)

32 Relative risk associated with exposure at 3 months of age (NDD): Autism (ICD9 2990) Presented at Simpsonwood and ACIP N = Relative risk < 37.5 ug (n=11) 37.5 ug (n=39) 50 ug (n=39) 62.5 ug (n=10) > 62.5 ug (n=28) Cumulative mercury exposure (and number of exposed cases(n)) Trend:1.005 (0.991, 1.019), p = 0.48

33 Relative risk + 95% confidence intervals (log scale) Relative risk associated with exposure at 3 months of age: Autism First presentation to IOM N = ccc 0 ug (n=3) 12.5 ug (n=1) 25 ug (n=5) 37.5 ug (n=57) 50 ug (n=58) 62.5 ug (n=12)> 62.5 ug (n=33) 1.52

34 Differences in cohorts and analyses Major reasons: Updated datasets with extended follow-up. Allowed additional cases to be identified in HMOs Exclusion criteria modified, based on scientific input from IOM, CDC and VSD investigators Improved adjustments for health-care seeking behavior Minor differences: Time of exposure Additional variables included in model

35 Review of Safety of Thimerosal-Containing Vaccines: a Two- Phased Study of Computerized Health Maintenance Organization Databases (Pediatrics 2003) Review of Verstraeten findings focused on autism Effects of inclusion/exclusion criteria upon autism findings Other subanalyses of autism-thimerosal Chronology of autism analyses Discussion of other concerns

36 Recent outside analyses of VSD data Performed using data at RDC We went to Atlanta,. "to the CDC, and looked at the VSD data. There is thimerosal-containing DTaP [diphtheria, tetanus and pertussis vaccine] and thimerosal-free DTaP, so we asked a question: Among children that got a minimum of either three consecutive thimerosalcontaining DTaPs or three consecutive thimerosal-free DTaPs, was there a difference in the number of autism cases in the two groups? We found mega differences. More than 20 times higher. The rate of autism in the children that got more than three doses of thimerosal-containing DTaP vaccines was much, much higher. Almost all the children that have autism in that group were the ones that got the thimerosal-containing DTaP vaccine. The more thimerosal the greater the cases of autism."

37 Attempted replications of recent outside analyses of VSD data Performed using data at RDC Limited to children born after 1997 (only children born after this date had chance of being given thimerosal-free vaccine) Looked at all children receiving DTPa vaccine 1/1/97-12/31/00 Exposure: total thimerosal dose from DTPa Outcome: first inpt or outpt autism diagnosis

38 Attempted replications of recent outside analyses of VSD data Performed using data at RDC Children were thus able to have 5 categories of exposure: 0 ug 25 ug 50 ug 75 ug >= 100 ug 76 cases of autism Controlled for gender Logistic regression

39 Attempted replications of recent outside analyses of VSD data Performed using data at RDC Exposure OR for Autism 0 ug (ref) 25 ug 4.81 ( ) 50 ug 4.75 ( ) 75 ug 6.72 ( ) >= 100 ug ( ) All OR are statistically significant at p < 0.05

40 Attempted replications of recent outside analyses of VSD data Performed using data at RDC Exposure Age at last f/u (median) 0 ug 1.03 yrs 25 ug 1.91 yrs 50 ug 1.82 yrs 75 ug 2.20 yrs >= 100 ug 2.92 yrs In other words, children with highest exposure had up to three times more opportunity to be diagnosed with autism.

41 Attempted Replications of recent outside analyses of VSD data Performed using data at RDC Reanalyzed this data Matched cases to controls on month and year of birth. Equalized groups according to length of follow-up and ability to be diagnosed with autism Deleted DTaP vaccines with unknown thimerosal content

42 Attempted Replications of recent outside analyses of VSD data Performed using data at RDC Follow up corrected by controlling for age (stratifying on year and month of birth) Exposure OR for Autism 0 ug ref 25 ug 1.10 ( ) 50 ug 0.93 ( ) 75 ug 0.75 ( ) >= 100 ug 1.21 ( )

43 Thimerosal and Neurodevelopmental Disorders: Institute of Medicine Causality Assessment The evidence is insufficient to accept or reject a causal association (July 2001) Hypothesis is biologically plausible The IOM recommended a portfolio of additional studies On-going CDC studies Follow-up neuropsychological testing study of children exposed to different levels of thimerosal as infants Follow-up study of vaccine clinical trial participants Case-control study of thimerosal and autism (planned)

44 Thimerosal and Autism: Next steps Large case-control study in final preparation stages Within Vaccine Safety Datalink Project In collaboration with Abt Associates External advisory board reviews protocol In depth examination of children with autism, along with extensive collection of data on: Prenatal mercury exposures Other environmental exposures

45 Thimerosal and Autism: Next steps Primary research questions: 1. Is there an association between cumulative exposure to Thimerosal from vaccines or RhoGAM from the prenatal period up through 7 months (214 days) of age, and autistic disorder? 2. Is the timing of children s exposure to ethg from Thimerosal in vaccines or RhoGAM related to autistic disorder?

46 Thimerosal and Autism: Comparison of VSD Screening Analysis and Planned Case-control Study Design Population Birth years Age (years) Exposure history Outcomes Outcome ascer. Screening Retro. cohort 2 HMOs (~1/4 < 3) Automated post-natal only AD Auto ICD-9 code Case-control Case-control 3 HMOs Auto, chart, interview pre and post-natal AD + ASD ADOS, ADI-R Confounding Limited control Detailed assess.

47 (Unadjusted) relative risks by increase of 12.5 ug ethylmercury HMO B tcome 0-1 m 2-3 m 4-5 m 6-7 m 0-7 m y neurodevelopmental disorder ** ** 1.05 * tism ildhood psychosis mmering * 1.21 * s * 1.18 * 1.14 * ep disorders ting disorders otional disturbances tention deficit disorder * 1.10 * * *: p<0.05 **: p<0.01

48 (Unadjusted) relative risks by increase of 12.5 ug ethylmercury HMO B(cont) tcome 0-1 m 2-3 m 4-5 m 6-7 m 0-7 m nguage delay 1.37 ** 1.20 ** * eech delay 1.10 * ** 1.05 * y renal disorder specified kidney and ureter ease ntrol diagnoses t feet or toe deformities ** * ury at unspecified site 0.78 ** * *: p<0.05 **: p<0.01

49 Safe Minds questions (on this analysis) Cohort size variations manipulated? Congenital/perinatal exclusions Exposure at 6 months low Young cohort Combination of disorders Differences HMOs Emotional disturbances: grouped vs separate

50 Limitations of using (administrative) computerized databases Misclassification exposure: HepB birthdose Misclassification outcome: ICD9 and Costar codes Unknown: medical care utilization factors Only conditions that come to medical attention

51 Attempted Replications of recent outside analyses of VSD data Performed using data at RDC Study by visiting investigator misclassified thimerosal content Vaccines with unknown codes were assumed to have 25 ug thimerosal, but most were thimerosal free (post-1997) Following analysis eliminated subjects with unknown vaccine content Exposure OR for Autism 0 ug (ref) 25 ug 6.45 ( ) 50 ug 6.27 ( ) 75 ug 8.45 ( ) >= 100 ug ( ) All OR are statistically significant at p < 0.05

Conceptual Framework for Follow-up Study of Thimerosalcontaining. Neurologic Developmental Disorders (NDDs) Paul A. Stehr-Green

Conceptual Framework for Follow-up Study of Thimerosalcontaining Vaccines and Neurologic Developmental Disorders (NDDs) Paul A. Stehr-Green Thanks to all CDC/ATSDR contributors ESPECIALLY: Bill Thompson